tbuckley/cabot-search huggingface dataset:
CNSC-04. CEREBROSPINAL FLUID-DERIVED CIRCULATING TUMOR DNA IS SUPERIOR TO PLASMA IN NSCLC PATIENTS WITH CNS PROGRESSION
Authors: Hainan Yang, Lei Wen, Caicun Zhou
Journal: Neuro-Oncology (2022)

Abstract Introduction Central nervous system (CNS) metastases are devastating neurologic complications. However, the clinical value of cerebrospinal fluid (CSF) as liquid biopsy medium in EGFR-mutated or ALK-rearranged patients with brain metastases (BM) or leptomeningeal metastases (LM) remains unclear. Patients and Methods We retrospectively analyzed the gene map of 14/48 NSCLC-BM patients and 34/48 NSCLC-LM patients. Compare the clinical predictive value of CSF and matched plasma (PLA) for patients with single CNS progression (cohort 1) or intracranial progression simultaneously with extracranial disease progression (cohort 2). Circulating cell-free tumor DNA (ctDNA) in CSF and matched PLA underwent next-generation sequencing targeting 168 cancer-relevant genes. Results For patients with single CNS progression, the mutation rate of major driver genes is much higher than the rate in matched PLA. Besides, CSF also demonstrated higher levels of potential prognostic markers in comparison with matched PLA samples, showing EGFR-amp presented more than two times the rate compared to matched PLA, and the detection rate of TBX3, PTEN were almost double the rate in CSF than paired PLA samples. In addition, poor outcomes associated with makers including CDKN2A/B, PIK3CA/G, CDK4/6, and MET showed exclusively in CSF samples.Almost all mutations identified in the PLA could detect in matched CSF samples in NSCLC-LM patients with both intracranial and extracranial disease progression. In addition, detection rates of driver mutations, consisting of EGFR or ALK are much higher in CSF compared to matched PLA, and these potential survival marker genes like CDK4/6, CDKN2A/B, EGFR-amp, MET, and PIK3CA identified uniquely in CSF samples. Conclusion CSF is more comprehensive in genomic mutation profile than matched PLA in NSCLC -LM regardless of single intracranial progression or intracranial progression simultaneously with extracranial evolution.
EXTH-96. BIOPROCESSING OF SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING
Authors: Emon Nasajpour, Geoff Lyle, Hope Lancero, Cesar Garcia, Katrina Learned, Eden Gibson, Caitlynn Tran, Troy Schouten, Hannes Vogel, Kelly Mahaney, Laura Prolo, Olena Vaske, Gerald Grant, Claudia Petritsch
Journal: Neuro-Oncology (2022)

Abstract Novel treatment approaches for pediatric central nervous system (CNS) tumors are urgently needed. A lack of patient-derived tumor cells impedes progress towards developing such new therapies. We intended to overcome this challenge by establishing methods to create a biorepository of viable single cell suspensions of pediatric brain tumor surgical specimens. Quantitative and qualitative comparisons of tissue processing strategies were performed to preserve viability of heterogeneous tumor and immune cells. Novel drug targets were identified by analyzing pathways affected by RNA transcripts that are highly expressed (outliers) in a patients’ tumor; outliers for each patient were determined by RNA-seq data from individual patients’ tumors compared with a compendium of 12,747 pediatric and adult samples harmonized by the Treehouse Childhood Cancer Initiative at the UCSC Genomics Institute. The predicted anti-tumor efficacy of small molecule inhibitors of the outlier pathways was tested in cell viability assays against short-term cultured cells from matched patients. Successful tissue collection required obtaining informed consent, standard operating procedures, and sample recording using a Laboratory Inventory Management Software (LIMS). Since 2020 we have banked 67 pediatric CNS brain tumor specimens at Stanford. Amongst those, 51 cases yielded sufficient tissue for RNA-seq and cryoprotection. The most common tumor histology was low-grade glioma (LGG, 26 of 67), the majority of which were pilocytic astrocytoma (18 of 26). The second and third most common tumor types are embryonal tumors (6 medulloblastoma, 3 AT/RT) and ependymoma (4), respectively. We identified significant differences in cell viability with different preservation media. An outlier pathway previously not implicated in LGG was identified and sensitivity to a small molecule inhibitor of this outlier pathway was demonstrated. Taken together, we established feasibility for validating therapeutic vulnerabilities identified by a genome-guided approach in short-term cultures from surgical specimens. This works facilitates the rapid development of personalized CNS tumor treatment.
NCMP-25. THE EFFECTS OF POLYPHARMACY IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Allison Hyde, Juliana Hernandez
Journal: Neuro-Oncology (2022)

Abstract Polypharmacy has been described as the use of five or more medications. With the effects of polypharmacy, patients may report difficulty with adherence to therapy, adverse drug-drug interactions, adverse drug-disease interactions, and cost. The development of cancer treatments for brain cancer is accomplished through clinical trials and the unfortunate truth is that most glioblastoma patients will have died in the time it can take to test a new treatment with more than half dying within the first 15 months of diagnosis. Upon completion, participants will be able to describe the effects of polypharmacy in patients with primary brain tumors in the outpatient setting. Additionally, participants will be able to identify the knowledge, skills, and attitudes necessary in the provision of nursing care to the patient with primary brain tumors. A working group comprised of two registered nurses in specialty neuro-oncology was formed. A knowledge, skills, ability framework was used to develop a survey to assess nurses' knowledge, skills, and attitudes regarding the effects of polypharmacy in patients with primary brain tumors. Two nurses were surveyed. Mean scores were calculated and ranked. The nurses reported important knowledge includes understanding of medication adverse and side effects, epidemiology and disease states including tumor histology. Important skills include neurological exam, triage, critical thinking, and patient education. The goal is to investigate the possibility of prioritizing care to include both a balance between treating the disease, use of concomitant medications and their associated adverse events. And in doing so encourage the individual to report an adverse event. In so doing this the patient is provided a wholistic treatment plan tailoring care to the individual. There was a stronger desire to better understand and manage these events.
QLTI-11. IMPROVING ACUTE STROKE RESPONSE AT A COMPREHENSIVE CANCER CENTER: A MULTIDISCIPLINARY HOSPITAL-BASED QUALITY IMPROVEMENT PROJECT
Authors: Wayne Quashie, Edward Avila, Melissa Barzola, Tara Buchholz, Jibran Majeed, Nicole Santa Maria, Lauren Schaff
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Stroke is common in patients with malignancy, but cancer patients in treatment have contraindications to intravenous (IV) tissue plasminogen activator (tPA). Advancements in endovascular therapy (EVT) has expanded options for acute stroke management . Memorial Sloan Kettering (MSK) is a cancer center without a public emergency room. Acute stroke management occurs inpatient or in urgent care center (UCC). We determined a need for rapid identification and management for acute strokes in our patient population. METHODS We developed a multidisciplinary Acute Stroke Pathway relying on activation of our hospital’s rapid response team (RRT), neurology, radiology, nursing support, patient escort services, and pharmacy. We initiated hospital-wide education around stroke symptoms and the pathway. All stroke activations are reviewed by Neurology bi-weekly for real-time feedback. Metrics include the times of symptom identification (“door time” = UCC check in or symptom discovery for inpatients), evaluation, head computed tomography (CT), labs, and administration of IV tPA. Times are compared to our 2016 institutional baseline data and National Institute of Neurological Disorders and Stroke (NINDS) benchmarks. RESULTS Since implementation of the pathway (6/11/2018) through Q1 2022 (3/31/2022), there were 551 acute stroke activations, 13 IV tPA administrations, and 48 patients transferred to a comprehensive stroke center for consideration for EVT. Average 2021 door-to-evaluation time: 8 mins (baseline: 18 mins, NINDS: 10 mins), door-to-stroke team: 11 mins (baseline: unknown, NINDS: 15 mins), door-to-CT: 33 mins (Baseline: 95 mins, NINDS: 25min), door-to-CT interpretation: 34 mins (baseline: 251 mins, NINDS: 45 mins), door-to-labs: 50 mins (baseline: unknown, NINDS: 45 min), door-to-IV tPA: 62 mins (baseline: unknown, NINDS: 60min). DISCUSSION The patient population at MSK is distinct from most hospitals. Patients with cancer have a higher incidence of stroke but are unlikely candidates for intervention. Inter-professional collaboration resulted in early stroke care in oncology patients consistent with NINDS benchmarks.
BIOM-11. ROR1 MRNA EXPRESSION IN GLIOMA - A NOVEL PROGNOSTIC BIOMARKER
Authors: Daniel Madani, Miya John, Laveniya Satgunaseelan, Brindha Shivalingam, Caroline Ford
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite maximal surgical resection followed by concomitant chemo-/radiotherapy, the three-year survival remains less than 5%. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) overexpression is associated with poor prognosis in several cancers. ROR1 therapeutics are in Phase I/II clinical trials making it an exciting novel target with translational potential to explore for glioblastoma treatment. The aim of this study was to examine the association between ROR1 mRNA expression and overall survival, by applying the WHO 2021 classification to transcriptomic glioma datasets. METHODS Clinical, histological, and molecular data was extracted from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Repository for Molecular Brain Neoplasia (REMBRANDT), and GSE16011 (GRAVENDEEL) projects via the GlioVis portal. Using the WHO 2021 classification, the dataset was appropriately re-classified. Only confirmed cases of astrocytoma, oligodendroglioma, or glioblastoma, and ROR1 mRNA expression data were included in the analysis, which included a total of 2,303 cases. 981 cases comprised the low-grade glioma cohort and 1322 cases were included in the high-grade glioma cohort. ROR1 mRNA expression from the four datasets was normalized within each dataset, combined, and divided into high and low expression groups. ROR1 expression and survival correlations were estimated with Kaplan-Meier survival analysis and Mantel-Cox test using GraphPad Prism v9. RESULTS Those with high ROR1 expression had an overall median survival of 4.5 months, as compared to 21.4 months in the low ROR1 expression cohort (p&amp;lt; 0.0001). High-grade gliomas had the highest ROR1 mRNA expression across the consortium when compared to the low-grade glioma cohort (p&amp;lt; 0.0001). CONCLUSION The results of this study indicate an association between overall survival in glioma and ROR1 expression. In addition, targeting ROR1 could hold translational importance for novel putative treatment in glioblastoma patients.
NCOG-22. TIGER PRO-ACTIVE STUDY: INVESTIGATING DAILY ACTIVITY, SLEEP AND NEUROCOGNITIVE FUNCTIONING IN GLIOBLASTOMA PATIENTS APPLYING TTFIELDS THERAPY IN GERMANY IN ROUTINE CLINICAL CARE
Authors: Martin Glas, Ghazaleh Tabatabai, Rainer Fietkau, Roland Goldbrunner, Oliver Bähr
Journal: Neuro-Oncology (2022)

Abstract Based on the EF-14 trial, Tumor Treating Fields (TTFields) therapy is recommended in treatment guidelines for newly diagnosed glioblastoma (GBM). However, real-world data are limited. The non-interventional TIGER study (NCT03258021) will give insight into patients’ therapy decision, TTFields therapy duration and usage, quality of life, overall survival, and adverse events (AEs) in the real-world setting. Subsequently, we have now established the TIGER PROgram, a collaborative national network of neurooncology centers, that will allow us to use previously established administrative structures for new real-world investigations. Also, it will enable a basic data set across different trials and thereby facilitate meta-analyses across different populations. Here we report on the first study that we initiated within this program, the TIGER PRO-Active Study (NCT04717739), a prospective, an ongoing non-interventional, multicenter study in Germany investigating changes in daily activity, sleep, neurocognitive functioning as potential quality of life parameter in GBM patients whilst receiving TTFields therapy. Furthermore, TTFields therapy usage and serious AEs will be evaluated. Based on the planned subgroup analysis (MGMT and age), the experiences with the ongoing TIGER trial, the expected dropout rate and in consideration of the Central Limit Theorem (sufficiently large group size of n ≥ 30) we will recruit approximately 500 adult patients with newly diagnosed GBM over the course of 2 years. Data on physical activity and sleep will be collected via specific smartphone apps. Neurocognitive functioning will be assessed using the MoCA (Montreal Cognitive Assessment) interview test and quality of life with the EORTC QLQ-C30 and -BN20 questionnaires. Data will be collected over a time period of at least 12 months. First results are expected in 2024.
SURG-08. COMBINED LOCAL TREATMENT OF BRAIN METASTASES: SURGERY AND POSTOPERATIVE STEREOTACTIC RADIOTHERAPY
Authors: Pavel Fadrus, Vaclav Vybihal, Vilem Juran, Ivana Roskova, Andrea Sprlakova-Pukova, Tereza Koprivova, Milos Kerkovsky, Radek Lakomy, Tomas Kazda, Ludmila Hynkova, Renata Belanova, Marek Vecera, Marketa Hermanova, Radim Jancalek, Jiri Sana, Ondrej Slaby, Pavel Slampa, Martin Smrcka
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Modern comprehensive local treatment of BM provides the possibility of adequate local control while maintaining a satisfactory quality of life. METHODS Patients after metastasectomy and postoperative radiotherapy treated between 2007-2020 were evaluated. Local control was assessed separately at the site of the operated MM (localPFS) and separately in other parts of the brain (distalPFS). RESULTS A total of 118 patients were enrolled (70 with WBRT), 54% were women, the median age was 60 years, the median performance status Karnofsky 80%. The most common primary tumor was lung carcinoma (39/118, 33%). Targeted stereotactic radiotherapy was significantly more often indicated in operations performed after 2016 (p &amp;lt; 0.001). In the period 2013-2019, gross total resection was achieved significantly more often (83 vs 64%; p = 0.061). The median follow-up is 49 months. The median overall survival (OS) is 9 months (6.2 - 12), the median localPFS 22 months (14 - unattainable), median distPFS 11 months (6.8 - 27 months), median extracranialPFS 11 months (5.9 - 15). Stratification of patients according to the prognostic index brainmetgpa.com led to significant separation of patients for OS (p = 0.00017). In a multivariate analysis, stereotactic radiotherapy was statistically significant positive prognostic factor for OS compared to WBRT (median OS 17 vs. 5.6 months, HR 0.59, p = 0.018) with no effect on localPFS. CONCLUSION Our results of comprehensive local treatment of BM are comparable with the results presented by important foreign studies from prestigious oncology centers. We described targeted stereotactic postoperative radiotherapy as an independent positive prognostic factor after brain metastasectomy. The study was supported by the programme project of the Ministry of Health of the Czech Republic with reg. no. NV18-03-00398, NV19-03-00501 and NV19-03-00559 and Supported by Ministry of Health, Czech Republic-conceptual development of research organization (FNBr, 65269705).
CSIG-33. BCOR LOSS PROMOTES RETINOBLASTOMA GROWTH AND DISSEMINATION BY MODULATING INSULIN-LIKE GROWTH FACTOR 2
Authors: Charles Eberhart, Lujain Alaali, Su Chan Lee
Journal: Neuro-Oncology (2022)

Abstract While loss of RB function is the most common genetic alteration in the pediatric embryonal eye tumor retinoblastoma, mutations leading to BCL-6 corepressor (BCOR) loss of function are the second most common alteration. BCOR mutations are found in more aggressive tumors, and are associated with metastasis and poor prognosis. We investigated the effects of BCOR loss or overexpression in retinoblastoma cells in order to better understand its functional role, and to determine if it represents a new therapeutic target in these tumors. Six established retinoblastoma cell lines were examined, and BCOR protein was most highly expressed in WERI-RB1, but absent in Y79 and two other lines. BCOR knock down in WERI-RB1 cells using shRNA caused markedly increased migration and proliferation. BCOR was also knocked out in these cells using CRSPR, resulting in more than three-fold increased size of intraocular murine xenografts and extensive extraocular extension of tumors. In terms of mechanism, BCOR loss of function induces IGF2 transcription, resulting in an activation of IGF1R and the ERK signaling pathway. In contrast, overexpressing BCOR in Y79 retinoblastoma cells with no baseline protein had opposite effects on IGF2. Targeting IGF2/IGF1R signaling pharmacologically using Lincitinib inhibited proliferation and migration in BCOR-negative retinoblastoma cells. Increased IGF2 transcription was regulated at least in part by hyper methylation of CCCTC-binding factor (CTCF)-binding regions in the IGF2/H19 imprinting control region (ICR), suggesting that BCOR knock down promotes increased methylation at this site. In summary, our studies revealed that BCOR loss promotes the growth and invasion of retinoblastoma cells in vitro and in vivo, at least in part via modulating IGF2 transcription, suggesting new potential therapeutic targets for these aggressive childhood tumors of the eye.
RADT-01. GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR PATIENTS WITH 10 OR MORE BRAIN METASTASES AT INITIAL CNS PRESENTATION
Authors: Bradley DePaoli, Serena Khaleghi, Edward Duffy, Michael Hall, Charlotte Rivers
Journal: Neuro-Oncology (2022)

Abstract Stereotactic radiosurgery (SRS) is an established treatment modality for patients with up to 10 brain metastases. Previous guidelines have recommended whole brain radiation therapy (WBRT) for patients with &amp;gt; 10 brain metastases, but many providers and patients have opted for SRS in an attempt to minimize neurocognitive toxicity. There is growing literature supporting SRS in patients with ≥ 10 brain metastases in both the up-front and salvage settings. Data remains limited in how to best manage patients with ≥ 10 brain metastases at their first central nervous system (CNS) presentation. A retrospective review was performed on all patients with ≥ 10 brain metastases at their first CNS presentation treated with Gamma Knife SRS since 2010 at our institution. Patients with prior surgery for neurological symptoms were included, but patients who had received prior CNS radiation were excluded. Patients could be treated in a single stage or as many stages necessary to treat all metastases. Demographics and clinical data were collected. Descriptive statistics were used to summarize variables. 91 patients were identified with a median age of 64 years old. The median brain metastases treated was 13 with a range of 10-57. Local failure was 11% and occurred at a median 10.8 months. Distant failure was 51.6% and occurred at a median 2.7 months. 30.8% of patients required repeat SRS and 18.7% of patients required salvage WBRT. Median survival was 7.2 months. 1-year and 2-year overall survival were 34.8% and 16.5%, respectively. Radiation necrosis occurred in 4.4%. Grade 2 toxicity occurred in 36.3% and Grade 3+ toxicity occurred in 7.7%. There were no grade 5 toxicities and only 5.5% of patients died from clear neurological causes. Upfront SRS provides acceptable local control, survival, and toxicity in patients with ≥ 10 metastases at CNS presentation and can be considered for first-line treatment.
MODL-13. Sensitivity of Tumor Treating Fields (TTFields) treatment planning to healthy tissue segmentation inaccuracies
Authors: Oshrit Ze’evi, Tal Marciano, Ariel Naveh
Journal: Neuro-Oncology (2022)

Abstract TTFields are FDA approved for treating patients with GBM. TTFields utilize low intensity electric fields with intermediate frequency (100-500 kHz) that disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields have been shown to disrupt multiple phases of the cell cycle including metaphase, anaphase, and telophase, resulting in cellular apoptosis. TTFields are administered through two pairs of capacitive arrays placed on the patient’s scalp. As TTFields are a dose dependent therapy, optimization of array layout for maximizing field intensity may improve survival rates of patients. Thus, Novocure is developing a treatment planning system, in which MR images are used to create a patient-specific model, which in turn is used for simulating electric fields distribution. However, the segmentation process of the MRIs is prone to errors that may influence the choice of array layout, and consequently provide lower TTFields dose than possible. To test the sensitivity of layout chosen to such inaccuracies, we placed different array layouts on the highly detailed MIDA head model and simulated the resulting LMiPD from each configuration. We then simplified the model in several phases and compared the resulting array layout ranking between the full model and each simplified model. Our results show that though the calculated LMiPD is very sensitive to the quality of the model, the ranking pattern between the detailed and simplified models is similar. Some alterations do occur, but this mostly happens when the LMiPD values between switched layouts are very close, rendering these alterations clinically insignificant. Based on these results, we conclude that the ranking order of array layouts by LMiPD dose does not significantly change between detailed and simplified head models even though the LMiPD dose itself is sensitive to the quality of the head model.